The effect of itraconazole and rifampicin on the pharmacokinetics of osimertinib

AimsWe investigated the effects of a strong CYP3A4 inhibitor (itraconazole) or inducer (rifampicin) on the pharmacokinetics of the epidermal growth factor receptor-tyrosine kinase inhibitor osimertinib, in patients with advanced non-small cell lung cancer in two Phase I, open-label, two-part clinical studies. Part one of both studies is reported. MethodsIn the itraconazole study (NCT02157883), patients received single-dose osimertinib 80mg on Days 1 and 10 and itraconazole (200mg twice daily) on Days 6-18 orally. In the rifampicin study (NCT02197247), patients received osimertinib 80mg once daily on Days 1-77 and rifampicin 600mg once daily on Days 29-49. ResultsIn the itraconazole study (n=36), the geometric least squares mean (GMLSM) ratios (osimertinib plus itraconazole/osimertinib alone) for C-max and AUC were 80% (90% CI 73, 87) and 124% (90% CI 115, 135), respectively, below the predefined no-effect upper limit of 200%. In the rifampicin study (n=40), the GMLSM ratios (osimertinib plus rifampicin/osimertinib alone) for C-ss,C-max and AUC were 27% (90% CI 24, 30) and 22% (90% CI 20, 24), respectively, below the predefined no-effect lower limit of 50%. The induction effect of rifampicin was apparent within 7 days of initiation; osimertinib C-ss,C-max and AUC values returned to pre-rifampicin levels within 3 weeks of rifampicin discontinuation. No new osimertinib safety findings were observed. ConclusionsOsimertinib can be co-administered with CYP3A4 inhibitors, but strong CYP3A inducers should be avoided if possible.